ERBB4 acts as a suppressor in the development of hepatocellular carcinoma
ERBB4 acts as a suppressor in the development of hepatocellular carcinoma
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ERBB4 在肝细胞癌的发展中充当抑制因子
DOI：
10.1093/carcin/bgx017
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发表时间：
2017-04-01
期刊：
影响因子：
4.7
通讯作者：
Li, Jianming
中科院分区：
文献类型：
--
作者：
Liu, Yao;Song, Liming;Li, Jianming
ERBB 4是表皮生长因子受体（EGFR）家族的成员之一，在生理和病理过程中起着关键作用。最近，我们发现ERBB 4对慢性B型肝炎病毒感染起保护作用。然而，ERBB 4在肝细胞癌（HCC）中的作用仍不清楚。在此，我们使用体外模型、体内动物模型和临床肝癌样本来探讨ERBB 4在肝癌发展中的作用。本研究中使用肝脏特异性ERBB 4敲除等位基因和除心脏敲除小鼠外的全ERBB 4。分别用四氯化碳（CCl 4）和二乙基亚硝胺（DEN）建立小鼠肝脏炎症和肿瘤模型。90例HCC患者的商业组织芯片与配对配对用于评估ERBB 4的表达和预后价值。通过微阵列分析研究了ERBB 4缺失背景下改变的基因，并通过实时PCR进一步验证。我们已经发现，ERBB 4在小鼠中的缺失导致更严重的损伤和肝肿瘤的形成，ERBB 4的缺失有助于肝细胞肿瘤的发展。在临床肝癌标本中，ERBB 4表达下调，对肝癌患者的预后有一定的预测价值。从机制上讲，ERBB 4的缺失通过抑制肿瘤抑制因子tp 53 inp 1的表达来抑制p53的表达。我们的研究揭示了ERBB 4作为HCC发展的抑制因子，并暗示了HCC中的ERBB 4-TP 53 INP 1-P53轴。
ERBB4, one member of the epidermal growth factor receptor (EGFR) family, plays a key role in physiological and pathological processes. Recently, we identified that ERBB4 played a protective role from chronic hepatitis B virus infection. However, the role of ERBB4 in hepatocellular carcinoma (HCC) is still unclear. Here, we explore the role of ERBB4 in the development of HCC using in vitro models, in vivo animal models and clinical samples of HCC. Liver-specific ERBB4 knockout alleles and full ERBB4 except heart knockout mice were used in this study. Liver inflammation and tumor models of mice were produced by carbon tetrachloride (CCl4) and diethylnitrosamine (DEN) administration, respectively. Commercial tissue arrays of 90 HCC patients with paired counterparts were used to evaluate the expression and the prognostic value of ERBB4. Genes altered in the setting of ERBB4 loss was studied by microarray analysis and further validated by real-time PCR. We have found that depletion of ERBB4 in mice leads to more severe injury and liver tumor formation and loss of ERBB4 contributes to the development of hepatocellular tumor. In clinic samples of HCC, ERBB4 is down-regulated and exhibit prognostic value of HCC patients. Mechanistically, loss of ERBB4 suppressed p53 expression by inhibiting the expression of the tumor suppressor tp53inp1. Our study uncovers ERBB4 as a suppressor in the development of HCC and implies an ERBB4-TP53INP1-P53 axis in HCC.